Bis-(Heteroarylmethoxyphenyl)cycloalkyl carboxylates as inhibitors of leukotriene biosynthesis

Abstract

Compounds having the structure <IMAGE> where m is an integer of from one to nine; n is an integer of from one to four; W is selected from substituted or unsubstituted quinolyl, benzothiazolyl, or quinoxalyl, X is selected from C1-6 alkylene, C2-6 alkenylene and C2-6 alkynylene; Y is selected from halogen, C1-6 alkyl and C1-6, alkoxy; and Z is selected from -C(O)B; -C(R2)2-O-N=A-C(O)B; and -C(R2)=N-O-A-C(O)B where A is C1-6 alkylene and B is -OH, -O-M+, -OD where D is a metabolically cleavable group, -OR6 where R6 is hydrogen or C1-6 alkyl, -NR6R7 where R7 is hydrogen, C1-6 alkyl, hydroxy or C1-6 alkoxy, or where R6 and R7 taken together form a five to eight membered ring optionally containing one heteroatom selected from nitrogen, oxygen or sulfur, are inhibitors of leukotriene biosynthesis.

We claim: 
     
       1. A compound having the structural formula I: ##STR38## or a pharmaceutically acceptable salt thereof wherein m is an integer of 1 to 9, inclusive; n is an integer of 1 to 4, inclusive;   W is the same at each occurrence and is selected from the group consisting of (a) unsubstituted quinolyl;   (b) quinolyl substituted with one, two, or three substituents selected from the group consisting of halogen,   C 1-6  alkyl, and   C 1-6  alkoxy;     (c) unsubstituted benzothiazoyl;   (d) benzothiazoyl substituted with one, two, or three substituents selected from the group consisting of halogen,   C 1-6  alkyl, and   C 1-6  alkoxy;     (e) unsubstituted quinoxalyl; and   (f) quinoxalyl substituted with one, two, or three substituents selected from the group consisting of halogen,   C 1-6  alkyl, and   C 1-6  alkoxy;       Y is one to four substituents independently selected from halogen,   C 1-6  alkyl, and   C 1-6  alkoxy;     X is absent or is selected from the group consisting of (a) C 1-6  alkylene;   (b) C 1-6  alkenylene; and   (c) C 1-6  alkynylene;     Z is selected from the group consisting of (a) COB;   (b) C(R 2 ) 2  --O--N═A--COB; and   (c) C(R 2 )═N--O--A--COB where A is C 1-6  alkylene, and   B is selected from the group consisting of (a) --OH,   (b) --O -  M +  where M is a pharmaceutically acceptable cation;   (c) --OR 6  where R 6  is hydrogen or alkyl of one to six carbon atoms;   (d) --NR 6  R 7  where R 6  is as previously defined and R 7  is selected from the group consisting of hydrogen,   alkyl of one to six carbon atoms,   hydroxy, and   alkoxy or from one to six carbon atoms, or   R 6  and R 7 , together with the atom to which   they are attached, form a ring of five to eight members containing one optional heteratom selected from N, and S; and     (e) --O--D where D is a metabolically cleavable group.         
     
     
       2. A compound as defined by claim 1 or pharmaceutically acceptable salt thereof wherein W is selected from the group consisting of unsubstituted quinolyl, and   quinolyl substituted with one, two, or three substituents selected from the group consisting of halogen,   C 1-6  alkyl, and   C 1-6  alkoxy.     
     
     
       3. A compound as defined by claim 1 or pharmaceutically acceptable salt thereof wherein W is selected from the group consisting of unsubstituted benzothiazolyl, and   benzothiazolyl substituted with one, two, or three substituents selected from the group consisting of halogen,   C 1-6  alkyl, and   C 1-6  alkoxy.     
     
     
       4. A compound as defined by claim 1 or pharmaceutically acceptable salt thereof wherein W is selected from the group consisting of unsubstituted quinoxalyl, and   quinoxalyl substituted with one, two, or three substituents selected from the group consisting of halogen,   C 1-6  alkyl, and   C 1-6  alkoxy.     
     
     
       5. A compound as defined by claim 1 or a pharmaceutically acceptable salt thereof wherein m is an integer of one to three, inclusive. 
     
     
       6. A compound as defined by claim 2 thereof selected from the group consisting of 4,4-bis-(4-(2-quinolylmethoxy)phenyl)cyclohexane carboxylic acid;   4,4-bis-(4-(2-quinolylmethoxy)phenyl)cyclohexane carboxylic acid sodium salt:   4,4-bis-(4-(2-quinolylmethoxy)phenyl)cyclohexyliminoxyacetic acid sodium salt;   4,4-bis-(4-(2-quinolylmethoxy)phenyl)cyclohexyliminoxy-2-propionic acid sodium salt;   4,4-bis-(4-(2-quinolylmethoxy)phenyl)-1-cyclohexylmethyliminoxyacetic acid; and   4,4-bis-(4-(2-quinolylmethoxy)phenyl)-1-cyclohexyloximinoacetic acid.   
     
     
       7. A pharmaceutical formulation comprising a leukotriene biosynthesis inhibitory effective amount of a compound as defined by claim 1 in combination with a pharmacutically acceptable carrier. 
     
     
       8. A method of inhibiting leukotriene biosynthesis in a mammal in need of such treatment comprising administering to said mammal a leukotriene biosynthesis inhibitory effective amount of a compound as defined by claim 1.